Insights into Hepatitis B Virus DNA Integration-55 Years After Virus Discovery

Overview

Journal Innovation (Camb)

Publisher Cell Press

Specialty Biomedical Engineering

Date 2021 Sep 24

PMID 34557710

Citations 27

Authors

Kaitao Zhao

Andrew Liu

Yuchen Xia

Affiliations

Soon will be listed here.

Abstract

Hepatitis B virus (HBV), which was discovered in 1965, is a threat to global public health. HBV infects human hepatocytes and leads to acute and chronic liver diseases, and there is no cure. In cells infected by HBV, viral DNA can be integrated into the cellular genome. HBV DNA integration is a complicated process during the HBV life cycle. Although HBV integration normally results in replication-incompetent transcripts, it can still act as a template for viral protein expression. Of note, it is a primary driver of hepatocellular carcinoma (HCC). Recently, with the development of detection methods and research models, the molecular biology and the pathogenicity of HBV DNA integration have been better revealed. Here, we review the advances in the research of HBV DNA integration, including molecular mechanisms, detection methods, research models, the effects on host and viral gene expression, the role of HBV integrations in the pathogenesis of HCC, and potential treatment strategies. Finally, we discuss possible future research prospects of HBV DNA integration.

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References

Staprans S, Loeb D, Ganem D . Mutations affecting hepadnavirus plus-strand DNA synthesis dissociate primer cleavage from translocation and reveal the origin of linear viral DNA. J Virol. 1991; 65(3):1255-62. PMC: 239899. DOI: 10.1128/JVI.65.3.1255-1262.1991. View

Liu S, Zhang H, Gu C, Yin J, He Y, Xie J . Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst. 2009; 101(15):1066-82. PMC: 2720989. DOI: 10.1093/jnci/djp180. View

Mason W, Liu C, Aldrich C, Litwin S, Yeh M . Clonal expansion of normal-appearing human hepatocytes during chronic hepatitis B virus infection. J Virol. 2010; 84(16):8308-15. PMC: 2916518. DOI: 10.1128/JVI.00833-10. View

Jones S, Boregowda R, Spratt T, Hu J . In vitro epsilon RNA-dependent protein priming activity of human hepatitis B virus polymerase. J Virol. 2012; 86(9):5134-50. PMC: 3347376. DOI: 10.1128/JVI.07137-11. View

Shafritz D, Shouval D, Sherman H, Hadziyannis S, Kew M . Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma. Studies in percutaneous liver biopsies and post-mortem tissue specimens. N Engl J Med. 1981; 305(18):1067-73. DOI: 10.1056/NEJM198110293051807. View

Walter E, Keist R, Niederost B, Pult I, Blum H . Hepatitis B virus infection of tupaia hepatocytes in vitro and in vivo. Hepatology. 1996; 24(1):1-5. DOI: 10.1002/hep.510240101. View

Liang T, Block T, McMahon B, Ghany M, Urban S, Guo J . Present and future therapies of hepatitis B: From discovery to cure. Hepatology. 2015; 62(6):1893-908. PMC: 4681668. DOI: 10.1002/hep.28025. View

Schweitzer A, Horn J, Mikolajczyk R, Krause G, Ott J . Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015; 386(10003):1546-55. DOI: 10.1016/S0140-6736(15)61412-X. View

Wang H, Wu H, Chen C, Fausto N, Lei H, Su I . Different types of ground glass hepatocytes in chronic hepatitis B virus infection contain specific pre-S mutants that may induce endoplasmic reticulum stress. Am J Pathol. 2003; 163(6):2441-9. PMC: 1892360. DOI: 10.1016/S0002-9440(10)63599-7. View

10.

Hirsch R, Lavine J, Chang L, Varmus H, Ganem D . Polymerase gene products of hepatitis B viruses are required for genomic RNA packaging as wel as for reverse transcription. Nature. 1990; 344(6266):552-5. DOI: 10.1038/344552a0. View

11.

Ng K, Chai S, Tong M, Guan X, Lin C, Ching Y . C-terminal truncated hepatitis B virus X protein promotes hepatocellular carcinogenesis through induction of cancer and stem cell-like properties. Oncotarget. 2016; 7(17):24005-17. PMC: 5029680. DOI: 10.18632/oncotarget.8209. View

12.

Barash H, R Gross E, Edrei Y, Ella E, Israel A, Cohen I . Accelerated carcinogenesis following liver regeneration is associated with chronic inflammation-induced double-strand DNA breaks. Proc Natl Acad Sci U S A. 2010; 107(5):2207-12. PMC: 2836653. DOI: 10.1073/pnas.0908867107. View

13.

Weber N, Stone D, Jerome K . TALENs targeting HBV: designer endonuclease therapies for viral infections. Mol Ther. 2013; 21(10):1819-20. PMC: 3808144. DOI: 10.1038/mt.2013.208. View

14.

Wang Q, Zhang W, Liu Q, Zhang X, Lv N, Ye L . A mutant of hepatitis B virus X protein (HBxDelta127) promotes cell growth through a positive feedback loop involving 5-lipoxygenase and fatty acid synthase. Neoplasia. 2010; 12(2):103-15. PMC: 2814349. DOI: 10.1593/neo.91298. View

15.

Xia Y, Guo H . Hepatitis B virus cccDNA: Formation, regulation and therapeutic potential. Antiviral Res. 2020; 180:104824. PMC: 7387223. DOI: 10.1016/j.antiviral.2020.104824. View

16.

Aziz K, Limzerwala J, Sturmlechner I, Hurley E, Zhang C, Jeganathan K . Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice. Gastroenterology. 2019; 157(1):210-226.e12. PMC: 6800187. DOI: 10.1053/j.gastro.2019.03.016. View

17.

Hai H, Tamori A, Kawada N . Role of hepatitis B virus DNA integration in human hepatocarcinogenesis. World J Gastroenterol. 2014; 20(20):6236-43. PMC: 4033461. DOI: 10.3748/wjg.v20.i20.6236. View

18.

Matsubara K, Tokino T . Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis. Mol Biol Med. 1990; 7(3):243-60. View

19.

Huang T, Zhang Q, Xie Q, Zeng L, Zeng X . Presence and integration of HBV DNA in mouse oocytes. World J Gastroenterol. 2005; 11(19):2869-73. PMC: 4305652. DOI: 10.3748/wjg.v11.i19.2869. View

20.

Mao Z, Bozzella M, Seluanov A, Gorbunova V . DNA repair by nonhomologous end joining and homologous recombination during cell cycle in human cells. Cell Cycle. 2008; 7(18):2902-6. PMC: 2754209. DOI: 10.4161/cc.7.18.6679. View